ECT is a highly effective treatment tar major depressive episodes (MDE), but cognitive side effects limit its use. This study attempts to isolate the neural pathways and physiological alterations associated with ECTs most significant side effect. retrograde amnesia. At baseline, patients with MDE often have reductions in global and regional cerebral blood flow (rCBF). Paradoxically, ECT further reduces resting rCBF and rCMR, and our preliminary data indicate that a particular topographic alteration is strongly associated with efficacy. However, our data also suggest that regional changes in resting rCBF, rCMR, and EEG following ECT are each linked to the magnitude of distinct amnestic effects. These pilot data challenge the traditional view that the amnestic effects of ECT are uniformly due to disruption of medial temporal lobe function. Rather, reduced temporopolar and prefrontal function may strongly contribute to retrograde amnesia (RA), the most persistent adverse effect of ECT. ECT provides a unique context in which to investigate the mechanisms and neural systems underlying long-term memory and retrograde amnesia, since patients can be studied both before and after they develop amnestic effects, as well as after recovery from amnesia. Forty patients with MDE and 20 matched normal controls will participate. The ECT methods selected from a randomized study will result in the greatest level of RA and yet produce marked indivudal differences in the magnitude of amnestic effects, without differences in efficacy. All participants will undergo fully quantitative 0-15 PET assessments of resting rCBF and rCBF response to cognitive challenge, consisting of cued recall of recent and remote personal (episodic) and non-personal, fact-based (semantic) memories, using a matched task paradigm. Both groups will undergo serial neurocognitive testing with a focus on retrograde memory. Assessments will be conducted at three time points, corresponding to preECT, 3-5 days postECT, and two-month follow-up in patients. The follow-up data will provide critical information on the long-term impact of ECT on brain functional activity and the relations between these changes and the resolution/persistence of amnestic deficits. In addition to providing key information about the neurophysiology of the amnestic effects of ECT, this study will advance our understanding of (a) the functional abnormalities in MOE, (b) the pathways that subserve autobiographical (episodic) memory in normal functioning, and (c) the pathways compromised in RA. Furthermore. this work should inform the development of new therapies that more focally modulate the neural systems implicated in therapeutic response. and avoid stimulation of the neural systems implicated in the development of RA.